Synthesis and evaluation of some new pyrazoline substituted benzenesulfonylureas as potential antiproliferative agents Pooja Rathore a , Shafiya Yaseen a , Syed Ovais a , Rafia Bashir a , Raed Yaseen a , Alhamzah D. Hameed a , Mohammed Samim a , Rakesh Gupta b , Firasat Hussain b , Kalim Javed a,⇑ a Department of Chemistry, Faculty of Science, Jamia Hamdard (Hamdard University), New Delhi 110 062, India b Department of Chemistry, University of Delhi, Delhi 110 007, India article info Article history: Received 6 December 2013 Revised 15 February 2014 Accepted 20 February 2014 Available online 28 February 2014 Keywords: Benzenesulfonylureas Pyrazolines Anti-cancer Antiproliferative activity Sulfonamides abstract Twenty six new pyrazoline substituted benzenesulfonylureas (2a–z) were synthesized and tested for in vitro anticancer activity. Fourteen derivatives (2i, 2k–2p, 2r, 2s–2x) were screened for their antiprolif- erative activity towards 60 human cancer cell lines by the National Cancer Institute (USA). Among them four compounds (2i, 2n, 2v and 2x) exhibited significant growth inhibition and further screened at 10- fold dilutions of five different concentrations (0.01, 0.1, 1, 10 and 100 lM). The compounds 2i, 2n, 2v and 2x showed effective growth inhibition (GI 50 MID) values of 2.62, 3.93, 3.33, 3.74 lM respectively beside cytostatic activity TGI (MG-MID) values of 8.42, 65.80, 24.00 and 36.06 lM respectively. The com- pound 2i displayed remarkable antiproliferative activity in 8 different cell lines with GI 50 less than 2 lM. Compounds 2n, 2v and 2x also displayed good antiproliferative activity against 11, 18 and 14 different cell lines respectively with GI 50 less than 3 lM. Ó 2014 Elsevier Ltd. All rights reserved. Cancer is a group of illness that results from cells in the body growing abnormally. These cells divide and produce new cells in an uncontrolled way that can spread throughout the body and cause damage to essential organs. Cancer treatment includes many strategies and chemotherapy plays a central role. 1 Chemotherapy involves the use of low-molecular-weight drugs to selectively de- stroy tumour cells or at least limit their proliferation. Despite im- mense advances in the field of basic and clinical research, which have resulted in higher cure rates for a number of malignancies, cancer remains the second leading cause of death after heart disor- ders in developing as well as advanced countries. 2 Although major advances have been made in the chemotherapeutic management of some patients, the continued commitment to the difficult task of discovering new anticancer agents remains critically important. Among the wide range of compounds tested as potential anti- cancer agents, derivatives comprising the sulfonamide, N 1 ,N 3 - diarylsulfonylurea and -thiourea functionalities have attracted great attention. 3,4 Recently three sulphonamides derivatives E7010, ER-34410 and E7070 (Fig. 1I–III) have been reported as po- tent antitumor agents and are in advanced clinical trials. 5 Sulofe- nur (Fig. 1IV) is a sulfonylurea that has been clinically evaluated in lung, breast, colon, ovarian, pancreatic and gastric cancer. 6 The antitumor properties of the diarylsulfonylurea is due to the uncou- pling of mitochondria 7,8 but other mechanisms, such as inhibition of the mitochondrial isozyme V of carbonic anhydrase (CA V), have also been hypothesized, since hydrolysis of the cytotoxic agent, leading to the formation of unsubstituted sulfonamides as the principal products, has been reported both in vivo and in vitro. 9 However, clinical trials of sulofenur have yielded unsatisfactory re- sults because of its high protein binding and dosing being limited by the appearance of anemia due to methemoglobinemia, a side effect likely associated with its aniline-related metabolites. 10 Pyrazol(in)e derivatives have attracting continuing attention over the years because of their broad spectrum biological activities and strong efficacy. Some representative of this heterocyclic exi- hibit antiproliferative, 11–13 anti-inflammatory, 14–16 anti-infec- tive, 17 antidepressant 18 and analgesic 19 activity. Recently, Lv et al., 11 discovered (V) (Fig. 1) displayed the most potent EGFR TK inhibitory activity with IC 50 of 0.06 lM, which was comparable to positive control Erlotirib. This compound (I) also showed significant antiproliferative activity against MCF-7 with IC 50 of 0.07 lM. The present work is an extension of our ongo- ing efforts towards developing promising biologically active agents using a hybrid pharmacophore approach. We made the design (Fig. 1) and synthesized hybrid compounds by linking pyrazoline ring system with benzene sulfonylurea. In these derivatives we http://dx.doi.org/10.1016/j.bmcl.2014.02.059 0960-894X/Ó 2014 Elsevier Ltd. All rights reserved. ⇑ Corresponding author. Tel.: +91 9873463272. E-mail addresses: kjaved@jamiahamdard.ac.in, kjavedchem@yahoo.co.in (K. Javed). Bioorganic & Medicinal Chemistry Letters 24 (2014) 1685–1691 Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl